U.S. patent number 8,211,368 [Application Number 13/113,787] was granted by the patent office on 2012-07-03 for conversion of nitrogen dioxide (no.sub.2) to nitric oxide (no).
This patent grant is currently assigned to Geno LLC. Invention is credited to David H. Fine, David P. Rounbehler, Gregory B. Vasquez.
United States Patent |
8,211,368 |
Fine , et al. |
July 3, 2012 |
Conversion of nitrogen dioxide (NO.sub.2) to nitric oxide (NO)
Abstract
A nitric oxide delivery system, which includes a gas bottle
having nitrogen dioxide in air, converts nitrogen dioxide to nitric
oxide and employs a surface-active material, such as silica gel,
coated with an aqueous solution of antioxidant, such as ascorbic
acid. A nitric oxide delivery system may be used to generate
therapeutic gas including nitric oxide for use in delivering the
therapeutic gas to a mammal.
Inventors: |
Fine; David H. (Cocoa Beach,
FL), Rounbehler; David P. (Las Cruces, NM), Vasquez;
Gregory B. (Cocoa, FL) |
Assignee: |
Geno LLC (Cocoa, FL)
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Family
ID: |
39788824 |
Appl.
No.: |
13/113,787 |
Filed: |
May 23, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20110240020 A1 |
Oct 6, 2011 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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12076723 |
May 24, 2011 |
7947227 |
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60896627 |
Mar 23, 2007 |
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60955767 |
Aug 14, 2007 |
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Current U.S.
Class: |
422/120;
128/204.21; 95/120; 128/203.12; 128/203.14; 422/122; 128/204.24;
95/102; 95/128 |
Current CPC
Class: |
A61P
9/10 (20180101); A61P 31/04 (20180101); A61P
7/00 (20180101); C01B 21/24 (20130101); A61M
16/10 (20130101); A61P 9/12 (20180101); A61P
11/00 (20180101); A61M 2016/1025 (20130101); A61M
2202/0275 (20130101) |
Current International
Class: |
A62B
7/08 (20060101); A61M 15/00 (20060101) |
Field of
Search: |
;422/120,122
;95/102,120,128 ;128/203.12,203.14,204.24,204.21 ;96/153,154 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0719159 |
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May 1997 |
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EP |
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WO 94/16740 |
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Aug 1994 |
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WO |
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WO 01/15738 |
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Mar 2001 |
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WO |
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Other References
Cooney et al., "Products of .gamma.-tocopherol with NO2 and their
formation in rat insulinoma (RINm5F) cells," Free Radical Biology
and Medicine, vol. 19, Issue 3, Sep. 1995, p. 259-269. cited by
other .
Material Safety Data Sheet, Silica gel, grade 41, 3-8 mesh MSDS
(created Oct. 9, 2005). cited by other .
Mascarenhas, Oscar Carlton, "Epoxy-Based Medical Grade Adhesive
Hydrogels and Nitric Oxide Releasing Polymers," Dissertation
Abstracts International, vol. 55/02-B, pp. 445 (1993). cited by
other .
Pulfer, Sharon Kay, "Nitric Oxide Releasing Polymers and Their
Application to Vascular Devices (Polyethyleneimine,
Polytetrafluoroethylene)," Dissertation Abstracts International,
vol. 56/12-B, pp. 6727 (1995). cited by other .
Roselle, Dominick C., et al., "Characterization and Nitric Oxide
Release Studies of Lipophilic 1-Substituted
Diazen-1-ium-1,2-Diolates," Journal of Controlled Release, vol. 51,
pp. 131-142 (1998). cited by other .
Smith, Daniel J. et al., "Nitric Oxide-Releasing Polymers
Containing the [N(O)NO] Group," Journal of Medicinal Chemistry,
vol. 39, No. 5, pp. 1148-1156 (1996). cited by other .
Taira, Msafumi, et al., "Continuous Generation System for
Low-Concentration Gaseious Nitrous Acid," Analytical Chemistry,
vol. 62, No. 6, pp. 630-633 (1990). cited by other .
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PCT/US02/27278 filed Aug. 28, 2002. cited by other .
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PCT/US05/029344 filed Aug. 18, 2005. cited by other .
Suzuki, "Nitrogen Oxides Generation Method for Recovered Nitric
Acid by Electrolysis. An action Plan for Reduction of
Low-Level-Liquid-Waste in Processing Plant," Kyoto Daigaku Genshiro
Jikkensho, (Tech Rep.) 1991, KURRI-TER-361, pp. 19-26. cited by
other .
Non-Final Office Action dated Apr. 8, 2005 for U.S. Appl. No.
10/229,026, filed Aug. 28, 2002; 17 pages. cited by other .
Tannenbaum, S.R. et al., "Inhibition of Nitrosamine Formation by
Ascorbic Acid," The American Journal of Clinical Nutrition,
American Society of Clinical Nutrition, Bethesda, Maryland, Jan.
1991, vol. 53, pp. 247-250. cited by other .
Licht, W.R. et al., "Use of Ascorbic Acid to Inhibit Nitrosation :
Kinetic and Mass Transfer Considerations for an in Vitro System,"
Carcinogenesis, IRL Press at Oxford University Press, Oxford, Mar.
1988, pp. 365-371. cited by other .
International Search Report for International Application No.
PCT/US08/03739 filed Mar. 21, 2008. cited by other.
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Primary Examiner: Bhat; Nina
Attorney, Agent or Firm: Steptoe & Johnson LLP
Parent Case Text
CLAIM OF PRIORITY
This application is a continuation of U.S. Ser. No. 12/076,723,
filed Mar. 21, 2008, now U.S. Pat. No. 7,947,227, issued on May 24,
2011, which claims the benefit of prior U.S. Provisional
Application No. 60/896,627, filed on Mar. 23, 2007 and prior U.S.
Provisional Application No. 60/955,767, filed Aug. 14, 2007, both
of which are incorporated by reference in its entireties.
Claims
What is claimed is:
1. A method of providing a therapeutic gas including nitric oxide
to a mammal comprising: connecting a permeation tube to a source of
nitrogen dioxide via a diffusion cell; connecting a receptacle to
the permeation tube, the receptacle including an inlet, an outlet,
and a surface-active material including an antioxidant, wherein the
inlet is configured to receive the flow of nitrogen dioxide from
the permeation tube; diffusing gaseous nitrogen dioxide from the
source of nitrogen dioxide into an air flow; communicating the air
flow to the outlet through the surface-active material; and
converting the gaseous nitrogen dioxide to nitric oxide at ambient
temperature.
2. The method of claim 1, wherein the source of nitrogen dioxide is
liquid nitrogen dioxide.
3. The method of claim 1, wherein the permeation tube length is
scaled to provide a predetermined dose of nitrogen dioxide at a
particular temperature.
4. The method of claim 1, wherein the permeation tube further
comprises a movable, non-permeable sheath over the length of the
tube.
5. The method of claim 4, further connecting the permeation tube to
the diffusion cell through a diffusion needle.
6. The method of claim 5, wherein the diffusion needle further
comprises holes on the side of needle and an outer sheath
surrounding the holes, wherein the sheath has slots fitted around
the needle configured to be turned to uncover the uncover the
desired hole.
7. The method of claim 1, further connecting the diffusion cell to
a plurality of permeation tubes through a plurality of narrow bore
diffusion needles.
8. The method of claim 1, wherein the surface-active material is
coated with the antioxidant.
9. The method of claim 1, wherein the surface-active material
comprises a silica gel.
10. The method of claim 1, wherein the antioxidant comprises
ascorbic acid.
11. The method of claim 1, wherein the antioxidant comprises alpha
tocopherol or gamma tocopherol.
12. The method of claim 1, wherein the receptacle is a first
receptacle, the method further comprising connecting a second
receptacle to the first receptacle, wherein the second receptacle
is configured to receive the flow from the first receptacle and
includes a second inlet, a second outlet, and a second
surface-active material including an aqueous solution of an
antioxidant and wherein the second inlet is configured and fluidly
communicates the flow to the second outlet through the second
surface-active material to convert the gaseous nitrogen dioxide to
nitric oxide at ambient temperature.
13. A method of providing a therapeutic gas including nitric oxide
to a mammal comprising: connecting a pressure regulator to a source
of nitrogen dioxide; attaching a receptacle to the pressure
regulator, the receptacle including an inlet, an outlet, and a
surface-active material coated with an antioxidant, wherein the
inlet is configured to receive the flow of nitrogen dioxide from
the permeation tube; communicating the flow to the outlet through
the surface-active material; converting the gaseous nitrogen
dioxide to nitric oxide at ambient temperature; and transporting
the therapeutic gas to a mammal.
14. The method of claim 13, further placing the receptacle on the
low pressure side of the pressure regulator.
15. The method of claim 13, the method further comprising
connecting a second receptacle to the first receptacle, wherein the
second receptacle is configured to receive the flow from the first
receptacle and includes a second inlet, a second outlet, and a
second surface-active material including an aqueous solution of an
antioxidant and wherein the second inlet is configured and fluidly
communicates the flow to the second outlet through the second
surface-active material to convert the gaseous nitrogen dioxide to
nitric oxide at ambient temperature.
16. The method of claim 13, wherein the pressure regulator includes
an inlet port and an outlet port that connects the receptacle with
a gas bottle having nitrogen dioxide in air.
17. The method of claim 13, wherein the surface-active material is
coated with the aqueous solution of the antioxidant.
18. The method of claim 13, wherein the surface-active material
comprises a silica gel.
19. The method of claim 13, wherein the antioxidant comprises
ascorbic acid.
20. The method of claim 13, wherein the antioxidant comprises alpha
tocopherol or gamma tocopherol.
Description
TECHNICAL FIELD
This description relates to controlled generation of nitric
oxide.
BACKGROUND
Nitric oxide (NO), also known as nitrosyl radical, is a free
radical that is an important signaling molecule in pulmonary
vessels. Nitric oxide (NO) can moderate pulmonary hypertension
caused by elevation of the pulmonary arterial pressure. Inhaling
low concentrations of nitric oxide (NO), for example, in the range
of 20-100 ppm can rapidly and safely decrease pulmonary
hypertension in a mammal by vasodilation of pulmonary vessels.
Some disorders or physiological conditions can be mediated by
inhalation of nitric oxide (NO). The use of low concentrations of
inhaled nitric oxide (NO) can prevent, reverse, or limit the
progression of disorders which can include, but are not limited to,
acute pulmonary vasoconstriction, traumatic injury, aspiration or
inhalation injury, fat embolism in the lung, acidosis, inflammation
of the lung, adult respiratory distress syndrome, acute pulmonary
edema, acute mountain sickness, post cardiac surgery acute
pulmonary hypertension, persistent pulmonary hypertension of a
newborn, prenatal aspiration syndrome, haline membrane disease,
acute pulmonary thromboembolism, heparin-protamine reactions,
sepsis, asthma and status asthmaticus or hypoxia. Nitric oxide (NO)
can also be used to treat chronic pulmonary hypertension,
bronchopulmonary dysplasia, chronic pulmonary thromboembolism and
idiopathic or primary pulmonary hypertension or chronic hypoxia.
Typically, the NO gas is supplied in a bottled gaseous form diluted
in nitrogen gas (N.sub.2). Great care has to be taken to prevent
the presence of even trace amounts of oxygen (O.sub.2) in the tank
of NO gas because the NO, in the presence of O.sub.2, is oxidized
to nitrogen dioxide (NO.sub.2). Unlike NO, the part per million
levels of NO.sub.2 gas is highly toxic if inhaled and can form
nitric and nitrous acid in the lungs.
SUMMARY
In one aspect, a kit for generating a therapeutic gas including
nitric oxide for use in delivering the therapeutic gas to a mammal
can include a diffusion cell configured to be connected to a source
of nitrogen dioxide, a permeation tube connected to the diffusion
cell, and a receptacle configured to attach to the permeation tube.
The receptacle can include an inlet, an outlet, and a
surface-active material coated with an antioxidant, wherein the
inlet can be configured to receive the flow of nitrogen dioxide
from the permeation tube and can fluidly communicate the flow to
the outlet through the surface-active material to convert the
gaseous nitrogen dioxide to nitric oxide at ambient temperature.
The source of nitrogen dioxide can be liquid nitrogen dioxide which
includes N.sub.2O.sub.4. The diffusion cell can be configured to
provide the nitrogen dioxide at a diffusion rate of 200,000 ng
(nanogram) per minute. The diffusion cell can be made of stainless
steel or plastic. The permeation tube length can be scaled to
provide a predetermined dose of nitrogen dioxide at a particular
temperature. The permeation tube can further include a movable,
non-permeable sheath over the length of the tube. The sheath can be
configured to be removed prior to use. The permeation tube can be
connected to the diffusion cell through a diffusion needle. The
diffusion needle can be a narrow bore diffusion needle. The
diffusion needle can further include holes on the side of needle
and an outer sheath surrounding the holes, wherein the sheath has
slots fitted around the needle configured to be turned to uncover
the uncover the desired hole. The holes on the side of the needle
can be at 1/4, 1/2 or 3/4 mark. The diffusion cell can be connected
to multiple permeation tube through multiple narrow bore diffusion
needles. The receptacle can include a cartridge. The surface-active
material can be saturated with the antioxidant. The surface-active
material can include a substrate that retains water. The
surface-active material can include a silica gel. The antioxidant
can include ascorbic acid, alpha tocopherol or gamma
tocopherol.
The receptacle is a first receptacle. The kit can further include a
second receptacle. The second receptacle can include its own inlet
and outlet, and a surface-active material coated with an aqueous
solution of an antioxidant, wherein the second inlet can be
configured to receive the flow from the first receptacle and can
fluidly communicate the flow to the second outlet through the
second surface-active material to convert the gaseous nitrogen
dioxide to nitric oxide at ambient temperature.
In another aspect, a kit for generating a therapeutic gas including
nitric oxide for use in delivering the therapeutic gas to a mammal
can include a pressure regulator configured to be connected to a
source of nitrogen dioxide, a receptacle configured to attach to
the pressure regulator, the receptacle including an inlet, an
outlet, and a surface-active material coated with an aqueous
solution of an antioxidant, wherein the inlet can be configured to
receive the flow from a source of gaseous nitrogen dioxide and can
fluidly communicate the flow to the outlet through the
surface-active material to convert the gaseous nitrogen dioxide to
nitric oxide at ambient temperature, wherein the receptacle can be
configured to attach to the gas bottle having nitrogen dioxide in
air or oxygen or some combination thereof, and capable of providing
a flow of gaseous nitrogen dioxide and air. The kit can further
include a gas bottle having nitrogen dioxide and capable of
providing diffusing gaseous nitrogen dioxide into an air flow. The
receptacle can be placed on the low pressure side of the pressure
regulator. The receptacle is a first receptacle. The kit can
further include a second receptacle. The second receptacle can
include its own inlet and outlet, and a surface-active material
coated with an aqueous solution of an antioxidant, wherein the
second inlet can be configured to receive the flow from the first
receptacle and can fluidly communicate the flow to the second
outlet through the second surface-active material to convert the
gaseous nitrogen dioxide to nitric oxide at ambient temperature.
The pressure regulator can include an inlet port and an outlet port
that connects the receptacle with a gas bottle having nitrogen
dioxide in air. The receptacle can include a cartridge. The
surface-active material can be saturated with the aqueous solution
of the antioxidant. The surface-active material can include a
substrate that retains water. The surface-active material can
include a silica gel. The antioxidant can include ascorbic acid,
alpha tocopherol or gamma tocopherol.
In a further aspect, a method of providing a therapeutic amount of
nitric oxide to a mammal can include diffusing nitrogen dioxide
into a gas flow, exposing the nitrogen dioxide to a surface-active
material coated with an antioxidant to convert the gaseous nitrogen
dioxide to nitric oxide at ambient temperature, and transporting
the nitric oxide in a therapeutic amount to a mammal. The nitrogen
dioxide can be generated from liquid nitrogen dioxide. The method
of providing a therapeutic amount of nitric oxide to a mammal
wherein diffusing nitrogen dioxide into a gas flow can include
providing the nitrogen dioxide at a diffusion rate of 200,000 ng
per minute. The method of providing a therapeutic amount of nitric
oxide to a mammal wherein diffusing nitrogen dioxide into a gas
flow includes providing a predetermined dose of nitrogen dioxide at
a particular temperature. The surface-active material can be
saturated with the antioxidant. The surface-active material can
include a substrate that retains water. The surface-active material
can include a silica gel. The antioxidant can include ascorbic
acid, alpha tocopherol or gamma tocopherol. The method of providing
a therapeutic amount of nitric oxide to a mammal can further
include contacting the nitric oxide a second surface-active
material coated with an antioxidant immediately prior to inhalation
by the mammal.
The details of one or more embodiments of the invention are set
forth in the accompanying drawings and the description below. Other
features, objects, and advantages of the invention will be apparent
from the description and drawings, and from the claims.
DESCRIPTION OF DRAWING
FIG. 1 is a block diagram of a cartridge that converts NO.sub.2 to
NO.
FIGS. 2-10 are block diagrams of NO delivery systems using the
cartridge of FIG. 1.
FIG. 11 is a diagram of another cartridge that converts NO.sub.2 to
NO.
FIGS. 12-14 are diagrams of NO delivery systems using the cartridge
of FIG. 11.
FIG. 15 is a block diagram of a NOx instrument calibration system
using the cartridge of FIG. 1.
FIG. 16 is a diagram showing placement of the GENO cartridge on the
low pressure side of the pressure regulator.
FIG. 17 is a diagram showing a cartridge that is an integral part
of a gas bottle cover.
FIG. 18 is a diagram showing a regulator connected to both the
outlet of the gas bottle and the inlet of the cartridge.
FIGS. 19-21B are diagrams showing aspects of a three-part cartridge
design.
FIGS. 22A-22B are diagrams showing implementations of a
recuperator.
FIG. 23 is a diagram of an NO delivery system using a GeNO
cartridge with a specially designed fitting.
FIG. 24 is a diagram of a diffusion cell connected to a permeation
tube.
FIG. 25 is a diagram of a permeation tube with a movable, sliding,
non-permeable sheath.
FIG. 26 is a diagram of a common diffusion chamber connected to
diffusion tubes, and permeation tubes.
DETAILED DESCRIPTION
When delivering nitric oxide (NO) for therapeutic use to a mammal,
it can be important to avoid delivery of nitrogen dioxide
(NO.sub.2) to the mammal. Nitrogen dioxide (NO.sub.2) can be formed
by the oxidation of nitric oxide (NO) with oxygen (O.sub.2). The
rate of formation of nitrogen dioxide (NO.sub.2) is proportional to
the oxygen (O.sub.2) concentration multiplied by the square of the
nitric oxide (NO) concentration--that is,
(O.sub.2)*(NO)*(NO)=NO.sub.2.
A NO delivery system that converts nitrogen dioxide (NO.sub.2) to
nitric oxide (NO) is provided. The system employs a surface-active
material coated with an aqueous solution of antioxidant as a simple
and effective mechanism for making the conversion. More
particularly, NO.sub.2 can be converted to NO by passing the dilute
gaseous NO.sub.2 over a surface-active material coated with an
aqueous solution of antioxidant. When the aqueous antioxidant is
ascorbic acid (that is, vitamin C), the reaction is quantitative at
ambient temperatures. The techniques employed by the system should
be contrasted for other techniques for converting NO.sub.2 to NO.
Two such techniques are to heat a gas flow containing NO.sub.2 to
over 650 degrees Celsius over stainless steel, or 450 degrees
Celsius over Molybdenum. Both of these two techniques are used in
air pollution instruments that convert NO.sub.2 in air to NO, and
then measure the NO concentration by chemiluminescence. Another
method that has been described is to use silver as a catalyst at
temperatures of 160 degrees Celsius to over 300 degrees
Celsius.
One example of a surface-active material is silica gel. Another
example of a surface-active material that could be used is cotton.
The surface-active material may be or may include a substrate
capable of retaining water. Another type of surface-active material
that has a large surface area that is capable of absorbing moisture
also may be used.
FIG. 1 illustrates a cartridge 100 for generating NO by converting
NO.sub.2 to NO. The cartridge 100, which may be referred to as a NO
generation cartridge, a GENO cartridge, or a GENO cylinder,
includes an inlet 105 and an outlet 110. Screen and glass wool 115
are located at both the inlet 105 and the outlet 110, and the
remainder of the cartridge 100 is filled with a surface-active
material 120 that is soaked with a saturated solution of
antioxidant in water to coat the surface-active material. The
screen and glass wool 115 also is soaked with the saturated
solution of antioxidant in water before being inserted into the
cartridge 100. In the example of FIG. 1, the antioxidant is
ascorbic acid.
In a general process for converting NO.sub.2 to NO, an air flow
having NO.sub.2 is received through the inlet 105 and the air flow
is fluidly communicated to the outlet 110 through the
surface-active material 120 coated with the aqueous antioxidant. As
long as the surface-active material remains moist and the
antioxidant has not been used up in the conversion, the general
process is effective at converting NO.sub.2 to NO at ambient
temperature.
The inlet 105 may receive the air flow having NO.sub.2 from an air
pump that fluidly communicates an air flow over a permeation tube
containing liquid NO.sub.2, such as in the system 200 of FIG. 2.
The inlet 105 also may receive the air flow having NO.sub.2, for
example, from a pressurized bottle of NO.sub.2, which also may be
referred to as a tank of NO.sub.2. The inlet 105 also may receive
an air flow with NO.sub.2 in nitrogen (N.sub.2), air, or oxygen
(O.sub.2). The conversion occurs over a wide concentration range.
Experiments have been carried out at concentrations in air of from
about 2 ppm NO.sub.2 to 100 ppm NO.sub.2, and even to over 1000 ppm
NO.sub.2. In one example, a cartridge that was approximately 6
inches long and had a diameter of 1.5-inches was packed with silica
gel that had first been soaked in a saturated aqueous solution of
ascorbic acid. The moist silica gel was prepared using ascorbic
acid (i.e., vitamin C) designated as A.C.S reagent grade 99.1% pure
from Aldrich Chemical Company and silica gel from Fischer
Scientific International, Inc., designated as S8 32-1, 40 of Grade
of 35 to 70 sized mesh. Other sizes of silica gel also are
effective. For example, silica gel having an eighth-inch diameter
also would work.
The silica gel was moistened with a saturated solution of ascorbic
acid that had been prepared by mixing 35% by weight ascorbic acid
in water, stirring, and straining the water/ascorbic acid mixture
through the silica gel, followed by draining. It has been found
that the conversion of NO.sub.2 to NO proceeds well when the silica
gel coated with ascorbic acid is moist. The conversion of NO.sub.2
to NO does not proceed well in an aqueous solution of ascorbic acid
alone.
The cartridge filled with the wet silica gel/ascorbic acid was able
to convert 1000 ppm of NO.sub.2 in air to NO at a flow rate of 150
ml per minute, quantitatively, non-stop for over 12 days. A wide
variety of flow rates and NO.sub.2 concentrations have been
successfully tested, ranging from only a few ml per minute to flow
rates of up to 5,000 ml per minute. The reaction also proceeds
using other common antioxidants, such as variants of vitamin E
(e.g., alpha tocopherol and gamma tocopherol).
The antioxidant/surface-active material GENO cartridge may be used
for inhalation therapy. In one such example, the GENO cartridge may
be used as a NO.sub.2 scrubber for NO inhalation therapy that
delivers NO from a pressurized bottle source. The GENO cartridge
may be used to remove any NO.sub.2 that chemically forms during
inhalation therapy. This GENO cartridge may be used to help ensure
that no harmful levels of NO.sub.2 are inadvertently inhaled by the
patient.
First, the GENO cartridge may be used to supplement or replace some
or all of the safety devices used during inhalation therapy in
conventional NO inhalation therapy. For example, one type of safety
device warns of the presence of NO.sub.2 in air when the
concentration of NO.sub.2 exceeds a preset or predetermined limit,
usually 1 part per million or greater of NO.sub.2. Such a safety
device may be unnecessary when a GENO cartridge is positioned in a
NO delivery system just prior to the patient breathing the NO laden
air. The GENO cartridge converts any NO.sub.2 to NO just prior to
the patient breathing the NO laden air, making a device to warn of
the presence of NO.sub.2 in air unnecessary.
Furthermore, a GENO cartridge placed near the exit of inhalation
equipment and gas plumbing lines (which also may be referred to as
tubing) also reduces or eliminates problems associated with
formation of NO.sub.2 that occur due to transit times in the
ventilation equipment. As such, use of the GENO cartridge reduces
or eliminates the need to ensure the rapid transit of the gas
through the gas plumbing lines that is needed in conventional
applications. Also, a GENO cartridge allows the NO gas to be used
with gas balloons to control the total gas flow to the patient.
Alternatively or additionally, a NO.sub.2 removal cartridge can be
inserted just before the attachment of the delivery system to the
patient to further enhance safety and help ensure that all traces
of the toxic NO.sub.2 have been removed. The NO.sub.2 removal
cartridge may be a GENO cartridge used to remove any trace amounts
of NO.sub.2. Alternatively, the NO.sub.2 removal cartridge may
include heat-activated alumina. A cartridge with heat-activated
alumina, such as supplied by Fisher Scientific International, Inc.,
designated as A505-212, of 8-14 sized mesh is effective at removing
low levels of NO.sub.2 from an air or oxygen stream, and yet lets
NO gas pass through without loss. Activated alumina, and other high
surface area materials like it, can be used to scrub NO.sub.2 from
a NO inhalation line.
In another example, the GENO cartridge may be used to generate NO
for therapeutic gas delivery. Because of the effectiveness of the
NO generation cartridge in converting toxic NO.sub.2 to NO at
ambient temperatures, liquid NO.sub.2 can be used as the source of
the NO. When liquid NO.sub.2 is used as a source for generation of
NO, there is no need for a pressurized gas bottle to provide NO gas
to the delivery system. An example of such a delivery system is to
described in more detail with respect to FIG. 2. By eliminating the
need for a pressurized gas bottle to provide NO, the delivery
system may be simplified as compared with a conventional apparatus
that is used to deliver NO gas to a patient from a pressurized gas
bottle of NO gas. A NO delivery system that does not use
pressurized gas bottles may be more portable than conventional
systems that rely on pressurized gas bottles.
FIGS. 2-14 illustrate techniques using silica gel as the
surface-active material employed in a GENO cartridge. As discussed
previously, silica gel is only one example of a surface-active
material that may be used in a NO generation system or
cartridge.
FIG. 2 illustrates a NO generation system 200 that converts liquid
NO.sub.2 to NO gas, which then may be delivered to a patient for NO
inhalation therapy. In general, a flow of air generated by an air
pump 205 is passed through a gas permeation cell 235 having liquid
NO.sub.2 and its dimer N.sub.2O.sub.4 (collectively, 236). The air
flow exiting the gas permeation cell 235 includes gaseous NO.sub.2,
which is converted to NO gas by a NO generation cartridge 240. The
NO gas mixture may be delivered to a patient for inhalation
therapy, for example, using a mask, a cannula, or a ventilator. The
concentration of NO in the NO gas mixture delivered to the patent
may be controlled by controlling the temperature of the gas
permeation cell 235 or the air flow rate through the flow meter
220.
More particularly, the system 200 includes an air pump 205, a
regulator 210, a flow diverter 215 and a flow meter 220. The system
is configured such that air flow 207 from the air pump 205 is
divided into a first flow 225 of 150 ml/min and a second flow 230
of 3000 ml/min. The air flow 207 may be dry or moist.
The flow 225 is passed through a gas permeation cell 235 containing
liquid NO.sub.2 and its dimer N.sub.2O.sub.4 (collectively, 236)
and a gas permeation tube 237. The permeation cell 235 also may be
referred to as a permeation generator, a permeation device or a
permeation tube holder. The NO.sub.2 diffuses through the gas
porous membrane of the gas permeation cell 235 into the flow 225.
In one example, the flow 225 of 150 ml/min of air is allowed to
flow through the permeation tube 237, such as a permeation tube
supplied by KinTek Corporation of Austin, Tex. The permeation tube
237 is designed to release NO.sub.2 at a steady rate such that the
gas stream leaving the permeation tube in the flow 225 contains
about 840 ppm of NO.sub.2 when the permeation tube 237 is at a
temperature of 40 degrees Celsius. The region 238 is temperature
controlled to maintain a temperature of approximately 40 degrees
Celsius. As discussed more fully below, maintaining the temperature
of the permeation cell 235 helps to control the concentration of NO
delivered to the patient.
The 150 ml of air containing 840 ppm of NO.sub.2 then flows through
a NO generation cartridge 240. In this example, the NO generation
cartridge 240 is 6 inches long with a diameter of 1.5 inches and
contains moist ascorbic acid on silica gel, which serves as the
conversion reagent. The NO generation cartridge 240 may be an
implementation of cartridge 100 of FIG. 1. The air stream 225
exiting from the NO generation cartridge 240 contains 840 ppm of
NO, with all or essentially all of the NO.sub.2 having been
converted to NO.
The 225 flow of 150 ml/min with 840 ppm NO then mixes with the flow
230 of 3000 ml/min of air or oxygen to produce a flow 247 of 3150
ml/min containing 40 ppm of NO. After mixing, the flow 247 passes
through a second NO generation cartridge 245 to remove any NO.sub.2
that may have been formed during the dilution of NO when the flows
225 and 230 were mixed. The NO generation cartridges 240 and 245
may be sized the same, though this need not necessarily be so. For
example, the NO generation cartridge 245 may be sized to have a
smaller NO.sub.2 conversion capacity than the NO generation
cartridge 240. The resulting flow 250 of air having NO is then
ready for delivery to the patient. The system 200 may be designed
to produce a steady flow of NO gas for a period as short as a few
hours or as long as 14 days or more. In one test, the system 200
was shown to deliver a steady flow of 40 ppm NO gas in air, without
NO.sub.2, for over 12 days, where the NO and NO.sub.2
concentrations were measured by a chemiluminescent gas
analyzer.
As an alternative to the system 200, a NO generation system may
include a permeation tube that has a larger flow capacity than the
permeation tube 237. In such a case, the larger permeation tube may
be able to process all of the inhaled air needed to be delivered to
the patient so that, for example, the flow 230 and the conversion
tube 245 are not necessary.
The system 200 can be made portable, for example, if the air pump
205 used to supply the air is a portable air pump, such as a simple
oil free pump. If oxygen-enriched air is needed by the patient,
oxygen can be supplied in addition to, or in lieu of, the air
supplied by the air pump 205. Oxygen can be supplied, for example,
from an oxygen tank or a commercially available oxygen generator.
Oxygen also can be supplied from a tank that has NO.sub.2 mixed
with O.sub.2.
In some implementations, the permeation cell 238 and/or the two
conversion cartridges 240 and 245 may be disposable items.
The concentration of NO in the flow 250 exiting the system 200 is
independent of the flow 225 through the permeation cell 235, as
long as the flow 225 is greater than a few milliliters per minute.
The concentration of NO in the flow 250 is a function of the
temperature of the permeation cell 235 and to a lesser degree the
air flow rate 230. For example, with a constant air flow rate 230,
the system 200 is designed to deliver 40 ppm NO at a temperature of
40 degrees Celsius; however, the concentration of NO can be reduced
to 20 ppm NO at 30 degrees Celsius and increased to 80 ppm NO at 50
degrees Celsius. As such, a temperature controller can be used to
adjust the concentration of the NO gas to be delivered. Once the
desired NO concentration is selected and the temperature controller
is set to maintain the particular temperature to deliver the
desired concentration, the delivery rate of NO gas at the desired
concentration remains constant. One example of a temperature
controller is an oven, such as an oven available from KinTek
Corporation, in which the permeation tube is placed. Another
example of a temperature controller is a beaker of de-ionized water
placed on a hot plate where the permeation tube is placed in the
beaker. A thermometer may also be placed in the beaker to monitor
the temperature of the water.
The NO generation system can be used to deliver a steady flow of NO
gas mixture for use with a cannula, with the excess gas being
vented to the environment. The NO generation system can be used
with a ventilator, and, in such a case, the delivery from the NO
generator must remain steady and cannot be shut off without
endangering the patient receiving the NO. To handle the increased
flow necessary during the air intake to the patient, the NO gas
mixture may be used to inflate and then deflate a flexible bag. If
the air flow to the patient is delayed in any way, a NO generation
cartridge can be inserted in the NO generation system at the point
immediately prior to inhalation to remove any NO.sub.2 that may
form from NO reacting with O.sub.2 during such a delay. This helps
to ensure that even very small amounts of NO.sub.2 that may be
formed in the bag during the delay are removed prior to the
therapeutic gas flow being inhaled by the patient.
A detector can be included in the therapeutic gas delivery system
200 to detect the concentration of NO in the therapeutic gas
stream. The detector can also detect the concentration of NO.sub.2
in the therapeutic gas, if necessary, and may provide a warning if
the NO concentration is outside a predetermined range or if the
concentration of NO.sub.2 is above a threshold value. Examples of
monitoring techniques include chemiluminescence and electrochemical
techniques. The presence of nitric oxide can be detected by, for
example, a chemiluminescence detector.
FIG. 3 depicts a NO generation system 300 that converts liquid
NO.sub.2 to NO gas, which then may be delivered to a patient for NO
inhalation therapy. In contrast to the NO generation system 200 of
FIG. 2, the NO generation system 300 includes an activated alumina
cartridge 345. The activated alumina cartridge 345 removes any
NO.sub.2 that forms during a delay. In contrast to the NO
generation cartridge 240, which removes the NO.sub.2 by converting
the NO.sub.2 to NO, and thereby quantitatively recovering the
NO.sub.2, the activated alumina cartridge 345 removes NO.sub.2 from
the process gas stream without generating NO.
FIG. 4 illustrates a therapeutic gas delivery system 400 that uses
a NO generation cartridge 440, which may be an implementation of NO
generation cartridge 100 of FIG. 1. The system 400 uses a NO source
410 to provide gaseous NO in a flow 420 through tubing. In one
example, the NO source 410 may be a pressurized bottle of NO. A
flow of air 430 through the tubing is generated by an air pump 435
and is mixed with the flow 420. The air flow entering the NO
generation cartridge 440 includes gaseous NO. Any NO.sub.2 gas that
may have formed in flow 420 is removed by the NO generation
cartridge 440. The air flow 450 exiting the NO generation cartridge
440 includes therapeutic NO gas but is devoid of toxic levels of
NO.sub.2. The air flow 450 then may be delivered to a patient for
NO inhalation therapy.
FIG. 5 illustrates a therapeutic gas delivery system 500 that uses
a NO generation cartridge 540, which may be an implementation of NO
generation cartridge 100 of FIG. 1. In contrast to therapeutic gas
delivery system 400 of FIG. 4, the system 500 generates NO from a
NO.sub.2 source 510. The NO.sub.2 source 510 may use diffuse liquid
NO.sub.2 in an air flow 515 generated by an air pump 520 such that
the flow 525 exiting the NO.sub.2 source 510 includes gaseous
NO.sub.2. In some implementations, NO.sub.2 source 510 may be a
pressurized bottle of NO.sub.2.
In any case, the air flow 525 entering the NO generation cartridge
440 includes gaseous NO.sub.2. The NO generation cartridge 440
converts the NO.sub.2 gas in flow 525 to NO. The air flow 550
exiting the NO generation cartridge 540 includes therapeutic NO gas
but is devoid or essentially devoid of NO.sub.2. The air flow 550
then may be delivered to a patient for NO inhalation therapy.
FIG. 6 illustrates a GENO pressure tank system 600 for delivering
therapeutic gas. The system 600 includes a tank 620 having 40 ppm
NO.sub.2 in air, which is commercially available, and a flow
controller 622. In one example of tank 620, a 300 cu. ft. tank
lasts 1.2 days at an air flow of 5 L/min.
An air flow 625a of NO.sub.2 in air exits the flow controller 622
and enters a GENO cartridge 640. The GENO cartridge 640 uses the
NO.sub.2 as a precursor and converts the NO.sub.2 to NO. The air
flow 625b exiting the GENO cartridge 640 includes therapeutic NO
gas. The air flow 625b enters an activated alumina cartridge 660 to
remove any NO.sub.2 in the air flow 625b. The air flow 625c that
exits the activated alumina cartridge 660 is delivered to a patient
for NO inhalation therapy.
The system 600 includes a NOx sample valve 665 and a NO-NO.sub.2
sensor 670 operable to detect NO.sub.2. A NO-NO.sub.2 sensor also
may be referred to as a NO-NO.sub.2 detector. The NOx sample valve
665 is operable to provide air samples from air flows 667a and 667b
to the NO-NO.sub.2 sensor 670. Using the NO-NO.sub.2 detector 670
to detect the presence of any NO.sub.2 in air flow 667a may provide
an indication of a failure of the GENO cartridge 640, and, as such,
provides a prudent safeguard to ensure that no toxic NO.sub.2 is
delivered to the patient.
In some implementations, the activated alumina cartridge 660 may be
replaced with a GENO cartridge.
In some implementations, the GENO cartridge is attached to the
output of a pressurized gas bottle that has special threads such
that the output from the gas bottle can only be interfaced to a
GENO cartridge. For example, the gas bottle may be filled with
breathable oxygen gas containing NO.sub.2 at a concentration of
about 10 to 100 ppm. Such a system may use the pressure of the gas
bottle to drive the therapeutic gas to the patient and may have no
moving parts, electronics or pumps. Alternatively, the gas bottle
may be filled with air that includes NO.sub.2 The use of air or
oxygen gas in the pressurized gas bottle may offer advantages over
a conventional method of providing NO in inert nitrogen gas, which
also necessitated the mixing and instrumentation needed to safely
dilute the concentrated NO gas to a therapeutic dose.
FIG. 7 illustrates a GENO high-concentration NO.sub.2 pressure
system 700 for delivering therapeutic gas. In contrast to the
system 600 of FIG. 6, the system 700 includes two GENO cartridges
740 and 750 and a switching valve 745 to control which of the GENO
cartridges 740 or 750 is used. When a NO-NO.sub.2 detector 770
detects the presence of NO.sub.2 in the air flow 725d exiting the
GENO cartridge being used, the switching valve 745 can be
manipulated to switch the air flow 725c to pass through the other
GENO cartridge 740 or 750. The ability to switch to a second GENO
cartridge in the event of failure of a first GENO cartridge
provides an additional layer of safety for the patient to whom the
therapeutic gas is being delivered.
More particularly, the system 700 includes a tank 720 having 1000
ppm NO.sub.2 in air and a flow controller 722. In the example, the
tank 720 is a 150 cu. ft. tank at 2250 psi and provides an air flow
of 125 cc/min. At an air flow of 5 L/min of 40 ppm delivered to the
patient, the tank 720 lasts approximately 23 days. The tank 720 is
able to provide an air flow for a longer period than the expected
life of each GENO cartridge 740 and 750, which is, in the cartridge
used in this example, less than two weeks. As such, the ability to
switch from one GENO cartridge to another GENO cartridge helps to
ensure that the contents of the tank are used or substantially
used.
An air flow 725a of NO.sub.2 in air exits the flow controller 722
and is mixed with an air flow 725b of 5 L/min that is generated by
an air source 730, such as an air pump. The resulting air flow 725c
enters the switching valve 745. The switching valve 745 controls
which of the GENO cartridges 740 or 750 receives the air flow 725c.
As shown, the switching valve 745 is set such that the air flow
725c is provided to the GENO cartridge 750. The GENO cartridge 750
converts the NO.sub.2 in the air flow 725c to NO. The air flow 725d
exiting the GENO cartridge 725d includes therapeutic NO gas. The
air flow 725d enters an activated alumina cartridge 760 to remove
any NO.sub.2 in the air flow 725d. The air flow 725e that exits the
activated alumina cartridge 760 is delivered to a patient for NO
inhalation therapy.
The system 700 includes a NO.sub.x sample valve 765 and an
NO-NO.sub.2 sensor 770 operable to detect NO.sub.2. The NO.sub.x
sample valve 765 is operable to provide air samples from air flows
767a and 767b to the NO-NO.sub.2 sensor 770. Using the NO-NO.sub.2
sensor 770 to detect the presence of any NO.sub.2 in air flow 767a
may provide an indication of a failure of the GENO cartridge being
used so that the second GENO cartridge may be used. In some
implementations, the activated alumina cartridge 760 may be
replaced with a GENO cartridge.
FIG. 8 illustrates a GENO high-concentration NO.sub.2 cartridge
system 800 for delivering therapeutic gas. In contrast to the
systems 600 or 700 of FIGS. 6 and 7, respectively, the system 800
includes a high-concentration NO.sub.2 cartridge as the source of
the NO.sub.2 used to generate the NO. More particularly, the system
800 includes an NO.sub.2 cartridge 800, such as a small butane tank
or a cartridge conventionally used to deliver CO.sub.2. In one
example of the system 800, a NO.sub.2 cartridge with dimensions of
1 inch by 6 inches and filled with 5% NO.sub.2 in CO.sub.2 was able
to deliver NO.sub.2 for 14 days.
A NO.sub.2 shut-off valve 821 is adjacent to the cartridge 800 to
shut-off delivery of NO.sub.2 from the cartridge 800. The system
800 also includes a flow controller 822 to ensure a generally
constant flow rate of the flow 825a exiting the flow controller
822. The flow controller 822 is a glass tube with a small hole
through which the gas flow 825a passes. In various implementations
of the system 800, the flow controller 822 may ensure a constant
flow rate of 1 to 10 cc/min.
The gas flow 825a having NO.sub.2 exits the flow controller 822 and
is mixed with an air flow 825b of approximately 5 L/min that is
generated by an air source 830. A gas mixer 835 ensures that the
air flows 825a and 825b are fully (or essentially fully) mixed. The
resulting air flow 825c with NO.sub.2 enters a GENO cartridge 840
that generates NO.
The system 800 also includes an activated alumina cartridge 860 to
remove any NO.sub.2 before the therapeutic gas including NO is
delivered to the patient at the rate of approximately 5 L/min. The
system 800 includes a NO.sub.x sample valve 865 and a NO-NO.sub.2
sensor 870 operable to detect NO.sub.2. In some implementations,
the activated alumina cartridge 860 may be replaced with a GENO
cartridge.
FIG. 9 illustrates a GENO permeation system 900 for delivering
therapeutic gas. The system 900 includes an air flow 925a of
approximately 5 L/min that flows into a GENO cartridge 940, which
acts to humidify the air. After exiting the GENO cartridge 940, the
air flow 925a divides such that an air flow 925b passes through a
permeation device 935 and an air flow 925c does not. The permeation
device 935 includes permeation tubing 937 and about 10 cc of liquid
NO.sub.2 936 when the air flow 925a begins. The permeation device
935 may be an implementation of the permeation cell 235 of FIG. 2.
The permeation device 935 is in a permeation oven 939 to maintain a
constant, or an essentially constant, temperature to ensure the
desired concentration of NO.sub.2 is diffused into the air flow
925b. The air flow 925b and the air flow 925c mix to form flow 925d
before entering the GENO cartridge 950. The GENO cartridge 950
converts the NO.sub.2 to NO.
The system 900 also includes an activated alumina cartridge 960 to
receive air flow 925e and remove any NO.sub.2 before the
therapeutic gas including NO is delivered to the patient at the
rate of approximately 5 L/min. The air flow 925f that exits the
activated alumina cartridge is delivered to a patient for NO
inhalation therapy. The system 900 includes a NO.sub.x sample valve
965 and a NO-NO.sub.2 sensor 970 operable to detect NO.sub.2.
FIG. 10 illustrates a GENO permeation system 1000 for delivering
therapeutic gas. In contrast to the system 900 of FIG. 9, the
system 1000 includes valves 1010 and 1015 to control which of the
GENO cartridges 1040 and 1050 first receives the air flow. The
system 1000 uses liquid NO.sub.2 in a permeation device 1035 as a
source of NO.sub.2 to be converted to NO. The system 1000 also
includes an activated alumina cartridge 1060 to remove any NO.sub.2
before the therapeutic gas including NO is delivered to the patient
at the rate of approximately 5 L/min. The system 1000 also includes
a NOx sample valve 1065 and a NO-NO.sub.2 sensor 1070 operable to
detect NO.sub.2.
The system 1000 receives an air flow 1025a of approximately 5 L/min
into the valve 1010, which, together with the valve 1015, controls
which of GENO cartridges 1040 or 1050 the air flow 1025a first
passes through. More particularly, by controlling the position of
the valves 1010 and 1015, the air flow 1025a can be made to pass
through the GENO cartridge 1040, the permeation device 1025, the
GENO cartridge 1050, and then the activated alumina cartridge 1060
before being delivered to the patient. By manipulating the position
of the valves 1010 and 1015, the air flow 1025a also can be made to
pass through the GENO cartridge 1050, the permeation device 1025,
the GENO cartridge 1040, and then the activated alumina cartridge
1060 before being delivered to the patient.
For example, when the NO-NO.sub.2 sensor 1070 detects the presence
of NO.sub.2 in the air flow 1025b, this may signal a need to
manipulate the valves 1010 and 1015 to cause the order in which the
GENO cartridges 1040 and 1050 are used to be switched--that is, for
example, when the air flow 1025a flows through the GENO cartridge
1040 before flowing through the GENO cartridge 1050, the values
1010 and 1015 are manipulated to cause the air flow 1025a to flow
through GENO cartridge 1050 before flowing through the GENO
cartridge 1040.
In some commercial applications, NO.sub.2 may be sold at a
predetermined concentration of approximately 10 to 100 ppm in
oxygen or air.
FIG. 11 illustrates a conceptual design of a GENO cartridge 1100
that converts NO.sub.2 to NO. The GENO cartridge 1100 may be an
implementation of the cartridge 100 of FIG. 1. The GENO cartridge
1100 is approximately 6-inches long with a 1-inch diameter. The
GENO cartridge 1100 includes silica gel saturated with an aqueous
solution of ascorbic acid and receives an air flow from an air or
oxygen gas bottle containing NO.sub.2. The air flow through the
cartridge 1100 converts NO.sub.2 to NO, which exits the cartridge
1100. The GENO cartridge 1100 works effectively at concentrations
of NO.sub.2 from 5 ppm to 5000 ppm. The conversion of NO.sub.2 to
NO using the GENO cartridge 1100 does not require a heat source and
may be used at ambient air temperature. The conversion of NO.sub.2
to NO using the GENO cartridge 1100 occurs substantially
independently of the flow rate of the air flow through the GENO
cartridge 1100.
FIG. 12 illustrates a therapeutic gas delivery system 1200 that
includes a gas bottle 1220 including NO.sub.2 and an GENO cartridge
1210, which may be an implementation of GENO cartridge 1100 of FIG.
11, for converting NO.sub.2 from the gas bottle 1220 to NO for
delivery to a patient for NO inhalation therapy. The system 1200 is
designed to be portable. In some implementations, the system 1200
may be designed to operate without the use of electronics or
sensors. Depending on the capacity of the gas bottle 1220, the
system 1200 generally has capability to deliver therapeutic NO gas
for one to sixteen hours.
The system 1200 may be employed to deliver therapeutic NO gas to a
patient on an emergency basis. Examples of such contexts include
use by paramedics, military medics or field hospitals,
firefighters, ambulances, and emergency rooms or a trauma center of
a hospital. In another example, a portable therapeutic NO gas
delivery apparatus may be used to assist a distressed mountain
climber, who may already be breathing oxygen-enriched air. In yet
another example, a portable therapeutic NO gas delivery apparatus
may be used for a patient whose primary NO source has failed. In
some implementations, a portable therapeutic NO gas delivery
apparatus may be designed for one-time use.
FIG. 13A depicts an exterior view 1300A of a therapeutic gas
delivery system with a liquid NO.sub.2 source. FIG. 13B illustrates
an interior view 1300B of the therapeutic gas delivery system shown
in FIG. 13A. The therapeutic gas delivery system includes a
permeation tube 1310 with a liquid NO.sub.2 source, which, for
example, may be an implementation of the permeation device 935 of
FIG. 9. The therapeutic gas delivery system also includes GENO
cartridges 1340 and 1350. The GENO cartridge 1340 receives an air
flow 1325a from an air or oxygen source. After exiting the GENO
cartridge 1340, the air flow is divided such that approximately 10%
of the air flow flows through the permeation tube 1310 by which
gaseous NO.sub.2 is diffused into the air flow. The air flow
exiting the permeation tube 1310 and the other air flow that did
not flow through the permeation tube 1310 flow through the GENO
cartridge 1350, which converts the NO.sub.2 to NO. The air flows
1325b and 1325c which exit the GENO cartridge 1350 are delivered to
the patient for NO inhalation therapy. The permeation tube 1310 and
the GENO cartridges 1340 and 1350 may be disposable.
Depending on the capacity of the permeation tube 1310, the
therapeutic gas delivery system shown in FIGS. 13A and 13B may have
the capability to deliver therapeutic NO gas for one to thirty
days.
The therapeutic gas delivery system shown in FIGS. 13A and 13B is
able to interface with a ventilator. The therapeutic gas delivery
system shown in FIGS. 13A and 13B also may be employed to deliver
therapeutic NO gas to a patient using a canella. For example,
delivery of the therapeutic NO gas may be provided through a
canella at a flow of 2 liters per minute. The use of the
therapeutic gas delivery system with a canella may enable NO
therapy to occur outside of a hospital setting. One such example is
the use of therapeutic gas delivery system for long-term NO therapy
that takes place at the patient's home.
FIG. 13C depicts the exterior view 1300A of the therapeutic gas
delivery system shown in FIGS. 13A and 13B relative to a soda can
1350. As illustrated, the implementation of the therapeutic gas
delivery system shown in FIGS. 13A-13C is a small device relative
to conventional NO inhalation therapy systems and is slightly
larger than a soda can.
FIG. 14 depicts an exterior view of a therapeutic gas delivery
system 1400 that uses GENO cartridges to convert NO.sub.2 to NO for
use in NO inhalation therapy. The system 1400 includes GENO
cartridge ports 1410 and 1415 through which a GENO cartridge may be
inserted or accessed. The system 1400 includes an inlet port 1420
through which air or oxygen flows into the system 1400 and an
associated gauge 1425. The system 1400 includes a flow value 1430
and display 1435 for controlling the air flow. The system 1400
includes GENO cartridge flow ports 1440.
The system 1400 also includes a temperature controller 1445 and a
NOx detector 1450, which is accessible through a NOx detector
access 1455. The system 1400 also includes a GENO cartridge 1460
that is used to convert NO.sub.2 to NO essentially just before the
air flow having NO exits the system 1400 through the outlet 1465.
The GENO cartridge 1460 may be referred to as a safety scrubber.
The GENO cartridge 1460 may be smaller than the GENO cartridges
used elsewhere in the system 1400. The system 1400 also includes a
backup input port 1470 and an exhaust fan 1475.
Additional Example Implementations
These additional example implementations use a gas bottle that
contains the required dose of NO, stored as NO.sub.2, in either
oxygen or air or some combination. The gas is converted on release
from the gas bottle as follows: Forward
2NO.sub.2.fwdarw.2NO+O.sub.2
This reaction takes place in under a second in the GENO cartridge
over Ascorbic acid on a moist silica gel matrix. The pressure of
the system should be held to that needed to force the gas through
the system. Typically, the force is about 0.01 to 50 psi. As soon
as the NO is formed, the reverse reaction occurs, namely: Reverse
NO+NO+O.sub.2.fwdarw.2NO.sub.2
The higher the pressure the faster this reaction occurs; indeed its
rate is 3.sup.rd order in pressure. Converting NO.sub.2 to NO on
the high pressure side of the regulator may not occur, when the
reverse reaction is occurring almost as fast as the forward
reaction. To address this challenge, the reverse reaction is
minimized by placing the GENO cartridge on the low pressure side of
the pressure regulator. This is shown in the FIG. 16 below. Gas
exits from the gas bottle, passes thru the regulator and then flows
down the first cartridge, up a connecting tube and then down a
second cartridge and then out to the user.
Two cartridges are used serially, one after the other. The reason
is to offer double redundancy. One cartridge works well, but having
a second cartridge provides redundancy. Each cartridge is sized to
take the entire contents of the gas bottle with from 40% extra
capacity at 100 ppm to 20.times. extra capacity for 20 ppm. As
such, this example implementation uses two identical cartridges,
which provides double the back up of the using only one
cartridge.
Operation and Safety
Another approach to increasing the safety of using the system is
shipping the cartridges as an integral part of the gas bottle
cover. This is shown in FIG. 17 below together with a
regulator:
In such an implementation, the user receives the gas bottle and
then attaches a special regulator to the gas bottle. Using
specially keyed CGA fittings, only a GENO regulator to could be
used. However, the output of the regulator may be shaped in such a
way as to become the inlet port to the GENO cartridge that is
attached to the gas bottle cover. Thus, the only way that the user
could get gas out of the bottle is to use a regulator with the
special CGA fitting, and the only way to get gas out of the
regulator would be to connect to the GENO cartridge. In this way,
the gas leaving the gas bottle only is able to pass through the
GENO cartridges.
This is depicted in FIG. 18. The cartridge remains with the gas
bottle at all times. For instance, even when the bottle is returned
to be refilled, the used cartridge remains on the gas bottle. The
gas filler then removes the spent cartridge and replaces the spent
cartridge with a new cartridge.
FIG. 18 shows the regulator connected to both the outlet of the gas
bottle and the inlet of the cartridge.
For further safety, the output from the cartridge may be keyed as
well so that the NO in oxygen gas can only be used with the special
adaptor.
In order to vary the concentration of the NO gas, a different gas
bottle is used. One way to help identify the concentration of the
NO gas in a gas bottle is to have bottles in each concentration
have a different color. For example, the bottle with 20 ppm
concentration would be blue, whereas the bottle with 100 ppm
concentration would be red. Each concentration could have its own
specially keyed gas bottles, which also may help reduce or prevent
unintentionally using a concentration of the NO gas that is
different than the intended concentration to be used. In order to
prevent a mix up at the gas bottler, different concentrations may
be bottled in different factories--for example, bottles with 100
ppm concentration are bottled at one location, whereas bottles of
20 ppm concentration are bottled at a different location.
In some implementations, the cartridge design may include only 3
parts. The first part is a twin tube with a third passage between
the twin tubes, as illustrated in FIG. 19.
FIG. 20 also depicts twin tubes with a third passage between the
twin tubes.
The end caps of this three-part cartridge design are shown below in
FIGS. 21A and 21B.
The interior of the caps is shaped to take the center tube. Sealing
the tubes to the caps to the tube may be accomplished with
ultrasonic welding. Sealing the tubes may be accomplished using
another technique, such as solvent bonding, O-rings or a clamp
seal. A feature of the caps is to mold the male part of the quick
disconnect right into the cap; thereby making the entire cartridge
a throw away item.
The cartridge may be assembled as follows: 1. A plastic frit, with
a pore size such that it holds the powder, is inserted into an end
cap. 2. The tube and one end cap are welded together, such that the
frit is positioned to act as a filter to prevent powder leaving the
cartridge. 3. The tube is filled with the reagent powder. During
filling the powder is compressed and vibrated so as to ensure
uniform and tight packing and the removal of all voids. Once the
tube is filled, the second end cap, with its filter held in place,
is placed over the top of the tube and welded in place. 4. If
needed, the system is flushed with nitrogen gas to eliminate oxygen
from the system. 5. Plastic end caps are placed over the inlet and
outlet tubes so as to prevent the entertainment of moisture.
Recuperator Cartridge
A recuperator cartridge is inserted into the gas plumbing line just
prior to inhalation. The purpose of the recuperator is to convert
back to NO gas any NO.sub.2 gas that may have been formed in the
ventilator and during storage in a gas bag or other temporary gas
storage device. FIGS. 22A and 22B illustrate other implementations
of a recuperator.
Alternatively, the recuperator may be the same size and form as one
of the first cartridges. This may further increase the safety of
the system in operation. For example, the recuperator would then
provide triple redundancy to the system with the recuperator being
able to convert the entire contents of the gas bottle from NO.sub.2
to NO.
Other Applications
The gas bottle can be used for other applications involving NO. The
gas bottle can be used to deliver the bottled gas without the use
of electronics. The advantages of the system include simplicity, no
mixing, no electronics and no software. To operate, the regulator
is connected and the valve opened.
The GENO gas bottle system can also be used with a dilutor. In an
example of implementation, the gas is shipped, for example, as 1000
ppm of NO.sub.2 in oxygen. In a first stage, the user's equipment
dilutes this concentration down to, perhaps, 20 ppm NO.sub.2. The
second stage inserts the GENO cartridge and converts the gas to NO.
A recuperator cartridge helps to reduce the user's concern to about
any NO.sub.2 that was formed in the gas lines because the NO.sub.2
would be converted by to NO by the recuperator. Similarly, the
recuperator cartridge could be used with existing system to convert
all of the residual NO.sub.2 gas being inhaled into the therapeutic
form, namely NO. The recuperator also ensures that no NO gas is
lost from the system and that the patient is receiving the full
prescribed dose.
The fact that GENO can deliver high doses of NO, of the order of
100 to 200 ppm or even higher, without the presence of the toxic
form, NO.sub.2, may be important. This addresses the difficulty of
a delivered dose being limited to around 20 ppm range due to the
presence of toxic NO.sub.2, which limited the dose that could be
achieved. The GENO system eliminates NO.sub.2 toxicity problems in
the inhaled gas. This may increase, perhaps even greatly increase,
the utility of NO gas for treatment of a multitude of diseases, and
especially ARDS ("Acute respiratory distress syndrome").
GENO Cartridge
NO.sub.2/O.sub.2 Gas Bottle Safety
In some implementations of the GeNO technology, NO.sub.2 is
dispensed at about 20 ppm in either oxygen or air and a GeNO
cartridge is built onto the high pressure side of the gas bottle.
The cartridge has the capacity to convert the entire NO.sub.2
(which is toxic) contents of the tank to NO gas, which is non toxic
(see FIG. 23). This high-pressure cartridge may be delivered with
the tank and designed to be removed only by the tank manufacturer,
due to a specially designed fitting. This cartridge also may have a
fitting for a regulator with a non-standard connection that permits
attachment of the GeNO cartridge (low-pressure) which, in turn, has
a connection for regular medical usage. This helps to prevent using
the tank without using the low-pressure cartridge, which is a
redundant safety cartridge that also has the capacity to convert
the entire contents of the NO.sub.2 in the tank. This also helps to
reduce the possibility that someone may attach a non-GeNO regulator
on a gas bottle containing toxic NO.sub.2 gas in oxygen or air, as
well as reducing the possibility of an accidental release of the
tank contents into a room in the absence of a regulator.
Backup System in Case of Primary Device Failure
Additionally or alternatively, a second, duplicate apparatus
(including tank, regulator and cartridge) is available to permit
rapid switching of the patient's input source to another tank.
Permeation Tube
Use of Diffusion Cell
A diffusion cell may help to minimize, or even alleviate, the risks
associated with a catastrophic rupture of the permeation tube. A
recommended dose of 20 ppm of NO in 5 liters of air per minute
amounts to about 0.33 g of NO.sub.2 per day. A 10 day supply could
have 3 to 4 g of liquid NO.sub.1/N.sub.2O.sub.4. If the permeation
tube were to rupture suddenly, the contents could escape into the
room, creating a serious hazard both for the patent and also for
the staff. To help mitigate this safety hazard, the liquid NO.sub.2
may be stored in a strong diffusion cell made of stainless steel or
a strong plastic. The diffusion cell is connected to the permeation
tube by means of a narrow bore hypodermic needle, and acts as the
reservoir for the permeation tube. In the event of a catastrophic
failure of the permeation tube, the liquid is released slowly over
hours to days through the narrow bore needle, thereby avoiding a
catastrophic and sudden release of toxic NO.sub.2. Furthermore, the
diffusion cell can be made strong enough to resist damage from, for
example, crushing, dropping onto concrete, or from sharp
objects.
Double Redundancy
In some implementations, the diffusion cell is designed to deliver
slightly more NO.sub.2 than needed by the permeation tube. Thus a
cell made of stainless steel with a 4 inch length of hollow tube of
0.002 inch id, would provide enough material to provide slightly
more than 20 ppm of NO.sub.2 in 5 liters of air per minute at 35
degrees Centigrade. The diffusion rate from the cell should be
about 200,000 ng per minute. If used in this way, the diffusion
cell acts not only as a safety device, but also as a back up
control release mechanism for the permeation tube. Even in the
event of a catastrophic and sudden failure of the permeation tube,
the diffusion cell continues to supply the appropriate dose. As
such, the diffusion tube is used as a storage device for a
permeation tube, and the permeation tube and the diffusion cell
work in tandem to provide double redundancy for safety. (See FIG.
24).
Temperature Effects on Permeation and Diffusion
The permeation rate and/or diffusion rate of NO.sub.2 from the
permeation tube and/or the diffusion cell is dependent upon the
temperature. In the case of NO.sub.2, the rate increases by a
factor of about 1.9 for every 10.degree. C. increase in
temperature. In the typical uses of permeation tubes and diffusion
cells, this rate increase is controlled by controlling the
temperature. For the GENO application, it may be desirable to
supply the gas in the temperature range of approximately 15 to 35
degrees C., without controlling the temperature. This may be
accomplished, for example, using the following concepts and
techniques.
Permeation tube. In a permeation tube, the amount of material that
can permeate is directly proportional to the length of the tube.
Thus, a longer tube can deliver more NO.sub.2 than a shorter one.
With this in mind, using a movable, sliding, non-permeable sheath,
one is be able to adjust the amount of permeation tube that is
exposed to regulate the delivery of NO.sub.2 for a given
temperature (see FIG. 25). The length of the tube is scaled to
provide the appropriate dose at the lowest design temperature. For
this example, the tube is designed to deliver approximately 200,000
ng/min at 15 degrees Centigrade. A sleeve is provided which slides
over the tube and covers about 3/4 of the length of the tube. Thus,
at 15 degrees Centigrade, the entire tube is exposed. If the
temperature were 25 degrees Centigrade, the rate of diffusion from
the tube is doubled, and this would be compensated for by covering
1/2 of the active length of the tube. At 35 degrees Centigrade,
only 1/4 of the tube would be needed to maintain the same
permeation rate of approximately 200,000 ng per minute.
It is contemplated that in a hospital environment where the
temperatures are well controlled, the system would be fitted with a
manual slide calibrated in degrees Centigrade, and the sheath would
be set at the temperature of the room. A thermometer could also be
attached to the device for added accuracy. A NO.sub.2 cartridge is
contemplated that includes a dial that is adjusted for a given
temperature in the patient's room that slides the sheath on the
permeation tube to the appropriate position, providing the
appropriate NO.sub.2 concentration for conversion to NO.
Diffusion Cell. The rate of release from the diffusion cell is
generally proportional to the length of the narrow bore diffusion
needle. In one approach, holes are present in the side of the
needle at the 1/4, 1/4, 3/4 marks. The three holes are offset so as
to be in the front, the side and the rear of the needle. An outer
sheath with the appropriate slots is fitted around the needle. By
turning the outer sheath, the hole at the 1/4 mark is uncovered at
15 degrees Centigrade, whereas all the side holes are covered at 35
degrees Centigrade.
In a second approach, the diffusion cell is fitted with four equal
narrow bore needles, with each needle being attached to a short
permeation tube. Using this approach, the number of tubes is
changed, depending upon the temperature.
In these example implementations, the number of tubes mentioned and
the number of holes are examples only and are not meant to limit
the application of the contemplated techniques.
NO Weaning-Off Dosage (5 ppm)
As with temperature control, the dosage can also be controlled by
using the sheath, or varying the number of tubes. A dial on one
tube may be attenuated to permit the release of a quarter of the
amount of NO.sub.2 (assuming full calibration is for a 20 ppm
dosage of NO) required to provide a 5 ppm weaning-off dosage of NO
to the patient. Additionally, if four tubes are used in the
NO.sub.2 cartridge to provide 20 ppm NO dosage, the dial can cover
three of the permeation tubes, leaving the fourth tube to provide
the 5 ppm dosage while permitting temperature adjustments (see FIG.
26). There are various permutations of this, based upon the
discussion provided above.
Rapid Equilibration
One of the challenges in using permeation tubes for medical dosage
is that they can take a long time to come to equilibrium. Because
the permeation tube is always permeating and cannot be switched
off, the tube may deliver an initial over dose if the tube was
sealed, without air flow, into its permeation chamber. It has been
observed to take four hours or more for the tube to reach
equilibrium and deliver the correct dose. By covering the active
area of the tube with an impermeable sheath, such as a heavy walled
Teflon or stainless steel or glass (see FIG. 25), the permeation of
the NO.sub.2 may be blocked during shipping and storage, and
substantially shortens, perhaps greatly shortens, the time needed
to achieve equilibrium. The sheath can be removed just prior to use
and generally 1 hour or less is needed to equilibrate to the
calibrated dosage. By covering the active area of the tube with an
impermeable sheath, equilibrium may be reached relatively more
quickly while helping to prevent an initial over dose that may
otherwise occur if the tube was sealed, without air flow, into its
permeation chamber while not being used for inhalation therapy.
Transport/Rupture Safety
Reinforcement of the diffusion chamber that contains the liquid
NO.sub.2, combined with the use of the diffusion cells also helps
to prevent the escape of toxic NO.sub.2 in the event of a
permeation tube rupture. Additionally, having the sheaths fully
lowered, sealing the permeation tubes from the NO.sub.2 cartridge
chamber during transportation and storage, and when not in use,
helps to provide protection for the tubes. The use of the sheaths
also protects the permeation tube when it is used without the
diffusion cell.
Transport/Temperature Safety
In some implementations, special heat sensitive ink can be put on
the NO.sub.2 cartridge to indicate exposure to overly high
temperatures. The ink notifies users not to use the cartridge,
since the heat might cause the permeation tubes to over-pressurize
and make them more sensitive to rupture. Air-tight seals on the
cartridge should help prevent pressure differentials between the
inside and outside of the permeation tubes.
Example 1
A cartridge six-inches in length with a diameter of 1.5-inches was
used as the NO generation cartridge. Approximately 90 grams 35-70
sized mesh silica gel was soaked in a 25% ascorbic acid solution
and air-dried at room temperature for two hours before being placed
in the cartridge. A NO.sub.2 permeation tube was used as the source
gas for NO.sub.2. Air from an air pump at a rate of 150 cc/min was
flowed into the permeation tube and mixed, after it exited the
cartridge, with 3 L/min of ambient air (which also was from the air
pump). The permeation tube was placed in an oven with a temperature
set at 32 degrees Celsius to provide a steady stream of 20 ppm
NO.sub.2 for the cartridge. The cartridge lasted for 269 hours
before ceasing to convert 100% of NO2 to NO, achieving
breakthrough.
Example 2
Two cartridges were each filled using 35-70 sized mesh silica gel
and approximately 40 grams of silica gel. The silica gel was
prepared by being soaked with a 25% solution of ascorbic acid until
complete saturation, and then dried in an oven for one hour at 240
degrees Fahrenheit. The ascorbic acid solution was prepared by
mixing 25 grams of ascorbic acid in 100 ml of de-ionized water.
A 1000 ppm NO.sub.2 tank was used to flow NO.sub.2 through the two
GENO cartridges at a rate of 150 cc/min. The two cartridges were
placed in series. Ambient air from an air tank was mixed in after
the NO.sub.2 had passed through the first cartridge and been
converted to NO. The air containing NO was then passed through the
through the second cartridge in series. The air was passed through
the cartridges at a rate of 3 L/min to create a total mixture of 40
ppm NO in air and free of any back reaction of NO.sub.2.
The two cartridges converted 100% of the NO.sub.2 for 104 hours. At
the end of 104 hours, the experiment was stopped because the
NO.sub.2 tank was empty. The two cartridges had not yet reached
breakthrough after 104 hours.
Results may be improved by drying the silica gel with a gas, such
as nitrogen gas, to remove dripping water/ascorbic acid solution
from the silica gel.
Example 3
A plastic PVC cartridge six-inches in length and having a diameter
of 1.5-inches was used as the NO generator cartridge. The inside of
the cartridge was filled with an ascorbic acid-silica mixture. To
create the ascorbic acid silica mixture, approximately 108 grams of
35-70 sized mesh was used. The silica gel was soaked in 25%
ascorbic acid solution and then baked in an oven for one hour at
240 degrees Fahrenheit. The ascorbic acid solution was prepared by
dissolving 25 grams of ascorbic acid in 100 ml of de-ionized
water.
A 1000 ppm NO.sub.2 tank was attached to one end of the cartridge
so that 1000 ppm of NO.sub.2 flowed through the cartridge at a rate
of 150 cc/min. The gas output of the cartridge was then mixed with
air using an air pump that flowed at a rate of 3 L/min to create a
total mixture of 40 ppm NO in air. This cartridge lasted for a
total of 122 hours before achieving breakthrough.
A NOx detector detected a slight concentration of NO.sub.2, varying
from 0.15 ppm to 0.25 ppm. The concentration of NO.sub.2 remained
steady until breakthrough, making it likely that the detected
NO.sub.2 concentration was not a failure in the 100% efficiency of
the cartridge but rather was NO.sub.2 that was recreated in tubing
after the cartridge. A second, smaller cartridge could be placed
before the detector to eliminate the small NO.sub.2 back
reaction.
Example 4
A cartridge was prepared by using 35-70 sized mesh silica gel
soaked in 25% ascorbic acid solution and air dried for
approximately one hour. A permeation tube was the source for the
NO.sub.2 and a KinTek oven was used to raise the level of NO.sub.2
required to 40 ppm. To achieve this concentration, the oven was set
at 45 degrees Celsius. Air was delivered to the permeation tube
using an air pump at the rate of 200 cc/min. Dilution air was also
provided by the air pump at the rate of 3 L/min. To add humidity to
the supply of NO.sub.2, two jars filled with water were attached to
the 200 cc/min air before the air entered the permeation tube. This
helped to ensure that the air entering the NO.sub.2 source would be
moisture rich and therefore that the NO.sub.2 entering the
cartridge would also be moisture rich. Approximately every five
days, the water in the first jar receded to below the end of the
tubing and needed to be replenished so that the water level was
above the bottom of the tube end. The second jar remained untouched
for the entire length of the experiment. The cartridge lasted for
409 hours before ceasing to convert 100% of NO2 to NO, achieving
breakthrough.
Example 5
A cartridge six-inches long and having a diameter of 1.5-inches was
prepared by using 108 grams of 35-70 sized mesh silica gel. The
silica gel was soaked in a 25% solution of ascorbic acid solution
and dried at room temperature (approximately 70 degrees Fahrenheit)
for approximately two hours. The air-dried silica gel was placed
inside the cartridge.
A flow of 40 ppm NO.sub.2 was sent through the silica-ascorbic acid
cartridge at a rate of 3.2 L/min. The cartridge lasted for 299
hours before ceasing to convert 100% of NO.sub.2 to NO, achieving
breakthrough. The cartridge filled with air-dried silica gel lasted
longer than a comparable cartridge filled with oven-dried silica
gel. This demonstrates oxidation losses due to heating the ascorbic
acid in the presence of air.
Example 6
Approximately 40 grams of 35-70 sized mesh silica gel was soaked in
a 33% ascorbic acid solution and the dried in an oven at 240
degrees Fahrenheit before being placed in the cartridge. Ambient
air at a flow rate of 3 L/min though an air pump was mixed with
1000 ppm of NO.sub.2 from a tank at a flow rate of 200 cc/min,
which created a total flow rate of 3.2 L/min and a total
NO.sub.2/air mixture of 60 ppm NO.sub.2. The cartridge lasted for
25 hours before losing its 100% conversion ability. This
demonstrates that using less silica gel/ascorbic acid in the
cartridge results in a cartridge that does not last as long.
The use of NO generation cartridge in which NO.sub.2 is
quantitatively converted to NO is not limited to therapeutic gas
delivery and may be applicable to many fields. For example, the NO
generation cartridge may be included in an air pollution monitor.
More particularly, the NO generation cartridge can also be used to
replace high temperature catalytic convertors that are widely used
today in air pollution instrumentation measurement of the airborne
concentration of NO.sub.2 gas. The current catalytic convertors
expend significant electricity, and replacement of a catalytic
convertor with a device that uses a NO generation cartridge may
simplify the air pollution instruments, and enable lower cost,
reduced weight, portable air pollution monitoring instruments.
In another exemplary use, a NO generation cartridge may be used in
a NOx calibration system. FIG. 15 illustrates an example of a NOx
calibration system 1500 that includes a tank 1520 having 1000 ppm
NO.sub.2 in air and a flow controller 1522. In the example of FIG.
15, the tank 1520 is an implementation of tank 722 in FIG. 7.
An air flow 1525a of NO.sub.2 in air exits the flow controller 1522
and is mixed with an air flow 1525b of 5 L/min that is generated by
an air source 1530, such as an air pump. The resulting air flow
1525c enters the switching valve 1545. The switching valve 1545
controls whether the GENO cartridge 1540 receives the air flow
1525c for conversion of the NO.sub.2 in the air flow 1525c to NO.
As shown, the switching valve 1545 is set such that the air flow
1525c, rather than being provided to the GENO cartridge 1540, is
provided to tubing 1550.
The system 1500 includes a NOx instrument 1570 that is to be
calibrated to detect NO and NO.sub.2. The NOx instrument 1570
receives the air flow 1525d that includes NO when the air flow
1525c is directed by switching valve 1545 to the GENO cartridge
1540. In contrast, the air flow 1525d includes NO.sub.2 when the
air flow 1525c is directed by switching valve 1545 to the tubing
1550.
The NOx calibration system 1500 requires a single pressurized tank
that includes NO.sub.2 to calibrate the NOx instrument 1570 for
both NO and NO.sub.2. To do so, for example, the NOx instrument
1570 first may be calibrated for NO by using the switching valve
1545 to direct the air flow 1525c through the GENO cartridge 1540
(which converts the NO.sub.2 in the air flow 1525c to NO). The NOx
instrument 1570 then may be calibrated for NO.sub.2 by using the
switching valve 1545 to direct the air flow 1525c through the
tubing 1550, which results in the air flow 1525d including
NO.sub.2. In addition, NOx calibration system 1500 does not require
the use of heat to convert NO.sub.2 to NO, for example, to ensure
that there is no inadvertent exposure to NO.sub.2 during
calibration.
Other implementations are within the scope of the following
claims.
* * * * *